Package for container of liquid medicine containing bicarbonate and pH indicator

ABSTRACT

The invention relates to a bicarbonate-containing medical solution package. The package comprises a gas-permeable plastic container holding a bicarbonate-containing medical solution and a gas-impermeable plastic packaging member containing the gas-permeable plastic container. A carbon-dioxide atmosphere is established in the space between the container and packaging member. In addition, a pH indicating device is contained within the space between the container and packaging member. The pH indicating device is a gas-permeable plastic packet containing a bicarbonate-containing fluid (similar to the medical solution) and a pH indicator. The pH indicator undergoes a change in color in response to a change in pH of the fluid. Use of this package allows the easy monitoring of a change in pH and consequent aging of the medical solution due to prolonged storage or damage to the outer packaging member.

TECHNICAL FIELD

The present invention relates to a bicarbonate-containing medicalsolution package and more particularly to an improvedbicarbonate-containing medical solution package equipped with anindicating device adapted to alert the user to expiration of a medicalaqueous solution containing sodium bicarbonate or the like through achange in color.

PRIOR ART

The medical bicarbonate solution, that is a medical aqueous solutioncontaining bicarbonate ions, is broadly in use in such applications asan antidote, an artificial kidney dialysate, a peritoneal dialysate, aninfusion, a root canal enlarging agent (for dental use), an artificialcerebrospinal fluid, an intraocular irrigating solution, a cardiacperfusate, a cardioplegic solution, a peritoneal irrigating solution, asolution for organ preservation, etc. In such a medical aqueoussolution, bicarbonate ions are in equilibrium as represented by thefollowing expression (1):

2HCO₃ ⁻CO₂↑+CO₃ ²⁻+H₂O

In an open system, the reaction proceeds to the right as the carbondioxide gas on the right-hand side of the expression is dissipated, withthe result that the bicarbonate ion is decreased and the carbonate ionis increased. As a result, the pH of the aqueous solution risesprogressively.

This change with time detracts a great deal from the utility value ofthe aqueous solution because one of the primary objectives of using sucha medical solution is the maintenance or correction of the acid-basebalance. Particularly, it is known that injection of the solution withan increased carbonate ion concentration causes necrosis of thesubcutaneous tissue [Howland, J. and Marriot, W. M., Am. J. Dis. Child.,11, 309 (1916)] and to avoid this hazard, the carbonate ionconcentration of solutions is generally controlled, with JapanesePharmacopoeia XIII restricting it to the range of 7.9-8.6 and USP 23 tothe range of 7.0-8.5.

Furthermore, to prevent aging, aqueous solutions for medical use areconventionally packed in gas-tight containers such as glass ampules orstoppered bottles for preventing evaporation of evolved carbon dioxidegas to thereby maintain the equilibrium essential to the stabilizationof bicarbonate ion concentration and solution pH.

However any glass container has the serious disadvantage that it isbroken by a slight impact, does not lend itself well to capacityincrease, is very heavy, and involves difficulties in disposal. Inaddition, since the evolution of carbon dioxide gas in the course ofsterilization or pasteurization of a medical aqueous solution isunavoidable, the risk for an elevation of internal pressure inducingbreakage of the glass container is high.

To overcome the above breakage and other troubles associated with glasscontainers and provide containers of reduced weight and easier todispose of, much research has been undertaken in the field of plasticcontainers in recent years and, for medical use, too, containers made ofpolyethylene, ethylene-vinyl acetate copolymer, polypropylene, polyvinylchloride, or the like have been developed. However, as usedindependently, plastic containers invariably have the disadvantage thatthe gas permeability of the plastic material itself is so high that whensuch a container is filled with a bicarbonate ion-containing aqueoussolution for medical use, the carbon dioxide gas evolved escapes throughthe container wall into the atmosphere with the progress of time toinevitably cause an elevation of the solution pH. Therefore, even theuse of such a plastic container is still inadequate for obviating theabove-mentioned disadvantages associated with aging of the solution. Theabove-mentioned problems due to dissipation of carbon dioxide gas andconsequent rising in pH of the solution are encountered in thesterilization step as well.

As a technology for overcoming the above-mentioned disadvantages ofplastic containers, it has been proposed to enshroud a direct containerin a gas-impermeable secondary container (outer container or packagingmaterial) and establish a carbon dioxide atmosphere in the space betweenthe two containers [e.g. Japanese Unexamined Patent Publication Nos.49675/1993, 261141/1993, and 339512/1994].

However, even this double packaging technology is not effective enoughto eliminate the gradual loss of carbon dioxide gas due to the incidenceof the so-called pinhole in the secondary packaging material or mereprolongation of the storage period and the aqueous solution which hasundergone such a time-dependent elevation of pH should be discardedpromptly to avoid the above-mentioned risk due to inadvertentadministration to a patient.

Regarding the detection of an abnormal pH change of such adouble-packaged bicarbonate-containing medical solution, much researchhas been undertaken and it has been proposed to dispose an oxygenabsorber, such as Ageless™ (manufactured by Mitsubishi Gas ChemicalCo.), and an oxygen sensor, such as Ageless Eye™ (manufactured byMitsubishi Gas Chemical Co.), within the secondary package to create ananoxic state and detect the infiltration of atmospheric oxygen in theevent of formation of a pinhole. However, this technology does notprovide for a direct indication of a pH change but merely senses theinfiltration of atmospheric oxygen from a pinhole. In addition, theabove-mentioned oxygen absorber and oxygen sensor have the drawback thatit requires a special handling procedure for avoiding exposure to oxygenduring storage as well as in the packaging operation. Therefore, theadvent of a technology that would lend itself well to commercialproduction and provide for an accurate and timely detection of pH changehas been demanded by the industry.

The present invention, therefore, has for its object to overcome all theabove-mentioned disadvantages of the prior art and thereby provide anovel medical solution package which is capable of holding abicarbonate-containing medical solution in stable condition in a plasticcontainer and providing an unmistakable visual indication of pH changedue to evolution of carbon dioxide gas.

After intensive studies with the above object in mind, the inventors ofthe present invention discovered that a novel medical solution packagemeeting the above object can be provided by the technology of theinvention which comprises a step of dispensing a bicarbonate-containingmedical solution in a gas-permeable plastic container and sterilizing itby the routine autoclaving, hot-water immersion, or hot-water showermethod or, as a alternative, dispensing a bicarbonate-containing medicalsolution in a plastic container by the aseptic process, a step ofpackaging the filled container in a gas-impermeable plastic secondarypackaging member, a step of establishing a carbon dioxide atmosphere inthe space between said container and said secondary packaging member,and a step of disposing a pH indicating device comprising agas-permeable plastic packet containing a bicarbonate-containing fluidand a specific pH-indicator within said space. The present invention hasbeen developed on the basis of the above finding.

DISCLOSURE OF THE INVENTION

Thus the present invention provides a bicarbonate-containing medicalsolution package comprising a gas-permeable plastic container filledwith a bicarbonate-containing medical solution and a gas-impermeableplastic packaging member enclosing said gas-permeable plastic container,with a carbon dioxide atmosphere having been established in a spacebetween said container and said packaging material, and, as disposed insaid space, a pH indicating device comprising a gas-permeable plasticpacket containing a bicarbonate-containing fluid and a pH-indicatorwhich undergoes a change in color in response to a change in pH of saidfluid.

More particularly, the present invention provides the above-mentionedpackage wherein said pH-indicator is a substance selected from amongcresol red, m-cresol purple, and phenol red, the above-mentioned packagewherein the pH-indicator is available in a concentration of 10-2000 ppm,the above-mentioned package wherein the bicarbonate concentration of thefluid within the pH indicating device is 0.05-2.0 w/v %, theabove-mentioned package wherein the bicarbonate is sodium bicarbonate,and the above-mentioned package wherein the carbon dioxide atmosphere isestablished by inclusion of a CO₂-generating oxygen absorber orenclosure of a CO₂-containing mixed gas.

Having the above-described construction, the package of the presentinvention offers the following and other advantages. Thanks to theutilization of a plastic container, it is not easily breakable,adaptable for increased capacity, and reduced in weight; because of theuse of a gas-impermeable secondary packaging member and establishment ofa carbon dioxide atmosphere in the space between said container andpackaging member, dissipation of the carbon dioxide gas released fromthe medical solution and the associated change in solution pH can beprevented; the pH change and associated aging of the medical solutionupon prolonged storage or due to formation of a pinhole in the secondarypackaging member can be easily detected by the naked eye; and theobjective package can be easily fabricated by the conventionalmanufacturing technology. Particularly in the present invention whereina bicarbonate-containing solution is used as an internal fluid of the pHindicating device, the pH of this internal fluid also changes inproportion with the change in pH of the medical solution in response tothe carbon dioxide concentration (CO₂ partial pressure) within thespace. Therefore, by using a pH-indicator capable of sensing a pH changeof the internal fluid, the pH change of the medical solution can bevisualized as the change in color of said pH-indicator.

The medical solution package of the present invention is now describedin detail. For use in the present invention, the bicarbonate-containingmedical solution may be any of aqueous solutions of a bicarbonate suchas sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate, orthe like, aqueous solutions containing such a salt or salts as well asother components and giving rise to bicarbonate ions, and aqueoussolutions of a carbonate, such as sodium carbonate, potassium carbonate,or the like, which give rise to carbonate ions (even if a carbonate isadded, it is converted to the corresponding bicarbonate at theapplication pH). The bicarbonate ion concentration of such aqueoussolutions need not be so critically controlled but is generally withinthe range of about 0.01-1 M, which corresponds to about 0.01-10% interms of the concentration of aqueous bicarbonate solutions. Theparticularly preferred bicarbonate concentration is about 0.1-8.5%.

The composition of said bicarbonate-containing medical solution is notrestricted but can be judiciously selected according to the intended useof the solution. Thus, it may be identical in composition to anantidote, an artificial kidney dialysate, a peritoneal dialysate, aninfusion, a root canal enlarging agent (for dental use), an artificialcerebrospinal fluid, an intraocular irrigating solution, a cardiacperfusate, a cardioplegic solution, a peritoneal irrigating solution, asolution for organ preservation, or the like or of a somewhat modifiedcomposition.

One of a typical bicarbonate-containing medical solution containselectrolyte ions and reducing sugar within the following formulationrange, and may additionally contain phosphate ions and trace metal ionssuch as copper and zinc ions.

Sodium ion 120-170 mEq/l Potassium ion 0-10 mEq/l Calcium ion 2-5 mEq/lMagnesium ion 0-3 mEq/l Chloride ion 100-150 mEq/l Bicarbonate ion 15-40mEq/l Reducing sugar 0-10 w/v %

As the gas-permeable plastic container to be filled with said medicalsolution, various containers which are conventionally used in themedical field can be employed. Thus, for example, containers made ofpolyethylene, ethylene-vinyl acetate copolymer, polypropylene, polyvinylchloride, or the like and those made of two or more suitable mixtures ofsuch resins or their laminates. There is no particular limitation on theshape and size of such containers but rectangular and cylindrical formsare generally preferred and their capacities are generally within therange of about 20 ml to about 3 litters. Such containers are used withadvantage in the present invention.

The above-mentioned container may be a gas-permeable plastic bagcomprising at least two intercommunicable compartments isolated from oneanother by a divider. Bags of this type are known. For example, a bagequipped with a closure means for preventing intercommunication of twocompartments (e.g. Japanese Examined Patent Publication No. 20550/1988,Japanese Examined Utility Model Publication No. 17474/1988) and a bagwhose compartments can be simply brought into intercommunication bypressing (e.g. Japanese Unexamined Patent Publication Nos. 309263/1988and 4671/1990). In such a bag, the bicarbonate-containing medicalsolution may be contained in at least one of the compartments.

The term “gas-impermeable” as used in describing the gas-impermeablepackaging member for use in the invention does not mean that theparticular material is strictly impermeable to gases, but is a relativeterm meaning that it is less permeable to gases than is theabove-mentioned container for a medical solution. Thus, even if thesecondary packaging member is made of the same material as that of thedirect container for a medical solution, it can be used as thegas-impermeable packaging material only provided it is sufficientlythick. The material that can be used for the gas-impermeable packagingmember includes all of those raw materials which are conventionally usedin the fabrication of packaging materials of this kind, such aspolyethylene terephthalate (PET), polyethylene naphthalate (PEN),polyvinyl alcohol (PVA), ethylene-vinyl alcohol copolymer (EVOH),polyvinylidene chloride (PVDC), and nylon, such plastic materialscarrying a vapor-deposition layer of inorganic material such as siliconoxide, aluminum oxide, etc. on the surface, and multi-layer compositematerials (laminates) made up of such materials. There is no particularlimitation on the shape and size of such packaging materials onlyprovided said plastic container can be suitably accommodated therein.However, it is necessary that, in shaped and size, such a packagingmember should provide for a sufficient space for accepting a carbondioxide-containing gas after packaging and generally speaking it ispreferably so large as to provide for a volume equal to about 1.2-3times the capacity of said plastic container.

Referring to the technology for establishing a carbon dioxide atmospherein the space between said container and packaging member, a typicalprocess comprises inspiriting a mixed gas, such as a mixture of CO₂ gasand air or a mixture of CO₂ gas and nitrogen gas, in said space. Thecarbon dioxide concentration of the mixed gas used in this process isselected according to the kind of medical solution to be contained inthe plastic container, particularly its bicarbonate ion concentrationand pH. Assuming, for instance, that said medical solution is an aqueoussolution prepared by dissolving 70 g of sodium bicarbonate in sufficientwater for injection to make 1 litter, the bicarbonate ion concentrationof this aqueous solution is 833 mM and the pH of the solution is 8.2. Tomaintain these values, the carbon dioxide concentration of the mixed gasatmosphere is preferably set to about 40%.

The bicarbonate ion concentration and pH of the medical solution for usein the present invention are generally about 0.01-1 M and pH about6.5-8.6, respectively. Preferably the carbon dioxide partial pressure insaid space is generally controlled at about 1 mmHg-760 mmHg and it ispreferable to select the percentage of carbon dioxide in said mixed gasaccordingly. More particularly, when the pH of the medical solutionimmediately after preparation is within the predetermined range, thecarbon dioxide gas to be enclosed in the space can be such that itspartial pressure will be substantially equal to the carbon dioxidepartial pressure of the medical solution.

An alternative method for establishing a carbon dioxide atmosphere inthe space defined by said container and packaging member comprisesenclosing a CO₂-generating oxygen absorber adapted to absorb the oxygengas in the space and release a predetermined proportion, by volume, ofcarbon dioxide. As examples of such CO₂-generating oxygen absorber,there can be mentioned Ageless G and Ageless GM, both manufactured byMitsubishi Gas Chemical Co., and Keep Fresh Type C manufactured byToppan Printing Co., Ltd.

The procedures for filling the container with the medical solution,sterilization, packaging with the secondary packaging member, andestablishment of a carbon. dioxide atmosphere within said space can allbe easily carried out in accordance with the routine production protocolfor injectable products.

It is one of the essential features of the present invention that a pHindicating device comprising a gas-permeable plastic packet enclosing abicarbonate-containing solution and a pH-indicator designed to undergo achange in color in response to a pH change of said solution is enclosedin the space within the bicarbonate ion-containing medical solutionpackage obtained as above. Here, only if the bicarbonate is contained,there is no particular limitation on the concentration and compositionof the internal fluid of the pH indicating device but its bicarbonateconcentration is preferably selected usually from the range of 0.05-2.0w/v %.

The pH-indicator to be incorporated in the above internal fluid of thepH indicating device can be selected from among a variety of acid-baseindicators which are capable of indicating a pH change of the deviceinternal fluid as a color change. Preferred is an indicator whichundergoes a change in color with high sensitivity in the pH region ofsaid device internal fluid at the equilibrium carbon dioxide gasfraction in said space which corresponds to the critical pH of themedical solution (the upper limit value according to JP for theproduct). Generally, the critical pH of-a medical solution is on thealkaline side as mentioned above (.for example, the specification upperlimit for a 7% aqueous solution of sodium bicarbonate is pH 8.6according to JP XIII and the corresponding carbon dioxide gas fractionis about 19%). The pH of the indicating device internal fluid which isproportional to the pH of the medical solution is also on the alkalineside (e.g. the pH of a 0.28% aqueous solution of sodium bicarbonate is7.0). Therefore, the above-mentioned pH-indicator is preferably acompound which undergoes a change in color on the weakly alkaline side.

The particularly preferred pH-indicator is one selected from among thosesubstances having the following characteristics, viz. (1) a narrow colorchange interval, (2) a high intensity of color, (3) a favorabledirection of color change (from an inconspicuous color to a conspicuouscolor), (4) high hygienicity (the substance should be highly safe andnot migratory), (5) high stability, with the initial color changeproperty being sustained for an extended time. As substances having suchcharacteristics, there can be mentioned neutral red, aurin, phenol red,o-cresol red, α-naphtholphthalein, m-cresol purple, orange I,phenolphthalein, etc. Among them, the more preferred are phenol red(change from yellow to red at pH 6.8 through 8.4), o-cresol red (changefrom yellow to red at pH 7.2 through 8.8), and m-cresol purple (changefrom yellow to purple at pH 7.6 through 9.2).

The concentration of said pH-indicator should only be such that itschange of color can be easily recognized by the naked eye and ispreferably selected, for example, from the range of about 10-2000 ppmaccording to the size of the packet (thickness of the fluid layer) inwhich it is enclosed together with the internal fluid.

The packet containing said internal fluid and pH-indicator can bemanufactured by the routine manufacturing technology and the rawmaterial for this gas-permeable plastic packet may be at leastequivalent to the medical solution container described hereinbefore ingas permeability. For example, said packet can be fabricated in acontinuous series of forming, filling, and sealing by means of avertical 3-side sealer, a vertical pillow packaging machine, or a rotarypacker. When this manufacturing method is employed, the raw material forthe packet is preferably a laminated film in consideration of machineprocessability and particularly when a polyethylene container is used asthe medical solution container, a polypropylene (outerlayer)-polyethylene (inner layer) laminate or a poly-4-methyl-1-pentene(outer layer)-polyethylene (inner layer) laminate is preferred.

Regarding the size of said packet and the volume of said internal fluid,it should be noted that if the quantity of the internal fluid enclosedin the packet is too small, the thickness of the indicating device fluidlayer will be insufficient to make a visual assessment of the colorchange difficult. Therefore, the packet size and internal fluid volumeshould be selected in consideration of the geometric relation of themedical solution container and the secondary packaging member as well asthe ease of recognition of the color change.

The indicating device thus prepared tends to develop turbidity owing togrowth of bacteria in the internal fluid upon prolonged storage and toprevent or control this clouding problem, it can be sterilized byautoclaving. As an alternative, an antiseptic such as benzalkoniumchloride, chlorhexidine gluconate, or the like, an antibacterial agentsuch as nalidixic acid, norfloxacin, etc., and/or a preservative such asp-hydroxybenzoic esters, benzyl alcohol, or the like may beincorporated.

Disposition of the packet in said space can be carried out simply bypackaging the medical solution container and the packet together in thesecondary packaging material and the disposing position is not criticalinasmuch as the packet may be visually recognized from outside thepackage. In this manner, there can be provided an improved medicalsolution package permitting a visual inspection of the pH change of themedical solution in accordance with the present invention.

One preferred example of the medical solution package of the inventionis illustrated in FIG. 1. This package comprises a gas-permeable plasticcontainer 2 holding a bicarbonate-containing medical solution (drugsolution, 1), a gas-impermeable packaging member 3 enclosing saidcontainer, and, as disposed in a space 4 defined by said container andpackaging member, a packet (pH indicating device) 5 containing abicarbonate-containing fluid and a pH-indicator, with a carbon dioxidegas atmosphere having been established within said space. Thanks to theabove construction, a visual assessment of the pH change of the medicalsolution, which is the object of the invention, is made feasible withthe accompanying merits mentioned hereinbefore.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view illustrating a medical solution packageaccording to one embodiment of the invention and

FIG. 2 is a diagrammatic representation of the pH-carbon dioxidefraction equilibrium curves of the medical solution and pH indicatingdevice internal fluid within the medical solution package of theinvention.

In the above view and diagram, the reference numeral 1 stands for amedical solution, 2 for a gas-permeable plastic container, 3 for agas-impermeable plastic packaging material, 4 for a space between saidcontainer 2 and packaging material 3, and 5 for a gas-permeable plasticpacket (pH indicating device).

EXAMPLES

The following pH indicating device production examples and the medicalsolution package examples are intended to describe the present inventionin further detail.

Production Example 1

In a 0.28% aqueous solution of sodium bicarbonate was dissolved 10 mg ofphenol red to make 500 ml (20. w/v ppm). Using a vertical 3-side sealer,a 0.5 ml portion of the above solution was packaged with a polypropylene(outer layer, 20 μm thick)-polyethylene (inner layer, 30 μm thick)laminated film to provide a pH indicating device, 30 mm by 15 mm (insidedimensions). This indicating device, freshly prepared, was red-purple(color already developed).

Production Example 2

In a 0.28% aqueous solution of sodium bicarbonate was dissolved 10 mg ofcresol red to make 500 ml (20 w/v ppm). A 0.5 ml portion of thissolution was packaged with a polyethylene film (manufactured by MitsuiPetrochemical; 250 μm thick) to provide a pH indicating device, 40 mm by20 mm (inside dimensions). Freshly prepared, this indicating device waspurple (color already developed).

Production Example 3

In a 0.28% aqueous solution of sodium bicarbonate was dissolved 10 mg ofm-cresol purple to make 500 ml (20 w/v ppm). Using a vertical 3-sidesealer, a 0.5 ml portion of the above solution was packaged with apolypropylene (outer layer, 20 μm thick)-polyethylene (inner layer, 30μm thick) laminated film to provide a pH indicating device, 30 mm by 15mm (inside dimensions). Freshly prepared, this indicating device waspurple (color already developed).

Production Example 4

In a 0.28% aqueous solution of sodium bicarbonate was dissolved 1 g ofm-cresol purple to make 50 l (20 w/v ppm). Using Bottlepack 305(manufactured by Rommelag), forming of a low-density polyethylenepacket, filling of a portion-of the above solution, and sealing werecontinuously carried out to provide a pH indicating device, about 20 mmby about 10 mm and about 0.4 mm in wall thickness (fluid volume: about0.4 ml).

Production Example 5

In a 0.28% aqueous solution of sodium bicarbonate was dissolved 1 g ofm-cresol purple to make 50 l (20 w/v ppm). Using a vertical 3-sidesealer, a 1 ml portion of the solution was packaged with an orientedpolypropylene (outer layer, 30 μm thick)-linear low-density polyethylene(inner layer, 60 μm thick) laminated film to provide a pH indicatingdevice having an external size of 40 mm by 20 mm and an internal size of30 mm by 12 mm. Until use, this indicating device was stored as packedtogether with a mixed gas of 10% CO₂-90% air in a bag made of nylon (15μm thick)-polyvinyl alcohol (18 μm thick)-low-density polyethylene (60μm thick) laminated film.

Production Example 6

Using a poly-4-methyl-1-pentene (outer layer, 30 μm thick)-polyethylene(inner layer, 60 μm thick) laminated film for packaging, the procedureof Production Example 5 was otherwise repeated to provide a pHindicating device. Because of the high heat resistance ofpoly-4-methyl-1-pentene, this product showed improved high-speedsealability for increased productivity. Until use, this pH indicatingdevice was stored together with a mixed gas of 10% CO₂-90% air in a bagmade of nylon (15 μm thick)-polyvinyl alcohol (18 μm thick)-low densitypolyethylene (60 μm thick) laminated film.

Example 1

A 7% sodium bicarbonate injection aseptically filled in a 20 ml plasticampule (mean thickness: 0.6 mm) made of low-density polyethylene(B-128H, Ube Industries) and adjusted to pH 8.3 was packed together withthe pH indicating device according to Production Example 1 and a mixedgas of 40% CO₂-60% air in a blister package (space volume 40 ml)consisting of a bottom sheet molded from a polypropylene (200 μm)-EVOH(ethylene-vinyl alcohol copolymer) (100 μm)-polypropylene (200 μm)laminated sheet and a cover made of PET (12 μm)-polyvinyl alcohol (14μm)-special grade polypropylene (40 μm) laminated film to provide amedical solution package according to the invention.

The indicating device was initially red-purple but had turned yellow(normal color) by 50 minutes later. The relation of the pH and carbondioxide gas fraction (%) of the medical solution in the above packageand the relation of the pH and carbon dioxide gas fraction of theinternal fluid of the indicating device are shown in FIG. 2.

It is clear from this diagram that the carbon dioxide fraction of themedical solution at the specification upper limit for pH (pH 8.6) isabout 19% and that the pH of the internal fluid of the pH indicatingdevice at the above carbon dioxide fraction is 7.0, which isapproximately equal to the color change region of 6.8-8.4 of phenol redused as the pH-indicator.

Using an injection needle (27G, Terumo, Neolus), a pinhole (about 500 μmin major diameter and about 50 μm in minor diameter) was pierced in thesecondary packaging member of the above medical solution package of theinvention and the change in color was monitored.

After 25 hours the indicating device was red-purple, and at this pointof time, the carbon dioxide gas fraction within the secondary packagewas 1.22% and the pH of the medical solution was 8.57 (the carbondioxide gas fraction within the ampule was 23.0%).

It has been found that the pH of such a medical solution then exceeds8.6 (deviation from the specification) within a short time and thisindicating device is useful for the prevention of use of an expiredmedical solution after its pH has deviated from the specification rangedue to formation of a pinhole in the secondary packaging member of theproduct.

Example 2

A 7% sodium bicarbonate injection aseptically filled in a 20 ml plasticampule (mean thickness: 0.6 mm) made of low-density polyethylene(B-128H, Ube Industries) and adjusted to pH 8.3 was packed together withthe indicating device according to Production Example 2 and a mixed gasof 40% CO₂-60% air in a bag of nylon (15 μm thick)-polyvinyl alcohol (18μm thick)-polyethylene (60 μm thick) laminated film (space volume: 40ml) to provide a medical solution package according to the invention.

The above indicating device was initially purple in color but had turnedyellow (normal color) by 40 minutes later.

Using an injection needle (27G, Terumo, Neolus), a pinhole (about 500 μmin major diameter and about 50 μm in minor diameter) was pierced throughthe secondary packaging member of the above medical solution package ofthe invention and the change in color was monitored.

After 23 hours the indicating device was purple in color and, at thispoint of time, the carbon dioxide gas fraction within the secondarypackage was 1.55% and the pH of the medical solution was 8.55 (thecarbon dioxide gas fraction within the ampule was 23.0%).

Example 3

A 7% sodium bicarbonate injection aseptically filled in a 20 ml plasticampule (mean thickness: 0.6 mm) made of low-density polyethylene(B-128H, Ube Industries) and adjusted to pH 8.3 was packed together withthe pH indicating device according to Production Example 3 and a mixedgas of 40% CO₂-60% air in a bag of nylon (15 μm thick)-polyvinyl alcohol(18 μm thick)-polyethylene (60 μm thick) laminated film (space volume 40ml) to provide a medical solution package according to the invention.

This indicating device was initially purple in color but had turnedyellow (normal color) by 50 minutes later.

Using an injection needle (27G, Terumo, Neolus), a pinhole (about 500 μmin major diameter and about 50 μm in minor diameter) was pierced throughthe secondary packaging member of the above medical solution package ofthe invention and the change in color was monitored.

After 32 hours the indicating device was purple and, at this point oftime, the carbon dioxide gas fraction within the secondary package was0.79% and the pH of the medical solution was 8.55 (the carbon dioxidegas fraction within the ampule was 24.2%).

Example 4

Five-hundred (500) milliliters of the following medical solution(Table 1) in a medical bag made of polyethylene (mean thickness: 250 μm)was sterilized by autoclaving (pH after sterilization: 7.30) and packedtogether with the indicating device according to Production Example 3and a mixed gas of 6% CO₂gas-94% air in a bag made of nylon (15 μmthick)-polyvinyl alcohol (12 μm thick)-LLDPE (40 μm) laminated film toprovide a medical solution package according to the invention.

TABLE 1 Bicarbonate-containing medical solution (/ml) Sodium bicarbonate1.94 mg Sodium chloride 7.24 mg Potassium chloride 0.05 mg Calciumchloride (dihydrate) 0.17 mg Magnesium chloride (hexahydrate) 0.23 mgGlucose 0.6  mg Potassium dihydrogen phosphate 0.15 mg Citric acid(additive) 0.32 mg

The indicating device disposed in the package of the invention, thusproduced, was initially purple in color but had turned yellow after 6hours.

Using an injection needle (27G, Terumo, Neolus), a pinhole (about 500 μmin major diameter and about 50 μm in minor diameter) was pierced throughthe secondary packaging member of the above medical solution package ofthe invention and the change in color was monitored.

After 103 hours the indicating device was purple, and at this point oftime, the carbon dioxide gas fraction within the secondary package was1.26% and the pH of the medical solution was 7.50.

Example 5

Five-hundred (500) milliliters of the medical solution (Table 1) in amedical bag (mean thickness: 250 μm) made of low-density polyethylenewas sterilized by autoclaving (pH after sterilization: 7.30) and packedtogether with one piece each of the pH indicating device according toProduction Example 3 and a oxygen absorber (Ageless GM-100 manufacturedby Mitsubishi Gas Chemical) in a bag made of nylon (15 μmthick)-polyvinyl alcohol (14 μm)-LLDPE (40 μm thick) laminated film toprovide a medical solution package according to the invention.

This pH indicating device was initially purple in color but had turnedyellow by 24 hours later.

Using an injection needle (27G, Terumo, Neolus), a pinhole (about 500 μmin major diameter and about 50 μm in minor diameter) was pierced throughthe secondary packaging member of the above medical solution package ofthe invention and the change in color was monitored.

After 10 hours, the indicating device was purple and at this point oftime the carbon dioxide gas fraction within the secondary package was1.36% and the pH of the medical solution was 7.45.

Example 6

A sodium bicarbonate injection aseptically filled in a 20 ml plasticampule (mean thickness 0.6 mm) made of low-density polyethylene (B-128H,Ube Industries) and adjusted to pH 8.3 was packed together with theindicating device according to Production Example 2 and a mixed gas of40% CO₂-60% air in a bag made of nylon (15 μm thick)-polyvinyl alcohol(18 μm thick)-polyethylene (60 μm thick) laminated film (space volume 40ml) to provide a medical solution package according to the invention.

The indicating device in the package was initially purple in color buthad turned yellow (normal color) by 6 hours later.

Using an injection needle (27G, Terumo, Neolus), a pinhole (about 500 μmin major diameter and about 50 μm in minor diameter) was pierced throughthe secondary packaging member of the above medical solution package ofthe invention and the change in color was monitored.

After 75 hours, the indicating device was purple and at this point oftime the carbon dioxide gas fraction within the secondary package was0.75% and the pH of the medical solution was 8.56 (the carbon dioxidegas fraction within the ampule was 18.1%).

Example 7

To the intercommunicable compartments of a two-compartment polyethylenebag (wall thickness: about 260 μm) equipped with a divider was filledwith the following medical solutions, respectively, and sealed and thesealed bag was sterilized by the hot-water shower method (the pH of amixture of the solutions after sterilization was 7.24). This bag waspacked together with the pH indicating device according to ProductionExample 5 and a mixed gas of 10% CO₂-90% air in a bag (secondary 5packaging material) made of nylon (15 μm thick)-silicon oxide-depositedpolyethylene terephthalate (12 μm thick)-polyvinyl alcohol (12 μmthick)-polyethylene (60 μm thick) laminated film (space volume 400 ml)to provide a medical solution package according to the invention.

Medical Solution Formulas (Compartment I) A solution containing thefollowing components in each 300 ml Calcium chloride dihydrate 0.17 gMagnesium chloride hexahydrate 0.22 g Glucose 0.61 g (Compartment II) Asolutiuon containing the following components in each 700 ml Sodiumchloride 7.15 g Potassium chloride 0.13 g Sodium bicarbonate 1.94 gPotassium dihydrogen phosphate 0.15 g

Using an injection needle (27G, Terumo, Neolus), a pinhole (about 500 μmin major diameter and about 50 μm in minor diameter) was pierced throughthe secondary packaging member of the above medical solution package ofthe invention and the change in color was monitored.

After 24 hours, the indicating device was purple and at this point oftime the carbon dioxide gas fraction within the secondary package was0.33% and the pH of a mixture of the solutions from the two compartmentswas 7.38.

Example 8

To the intercommunicable compartments of a two-compartment polyethylenebag (wall thickness: about 260 μm) equipped with a divider was filledwith the following medical solutions, respectively, and sealed and thesealed bag was sterilized by the hot-water shower method (the pH of amixture of the solutions after sterilization was 7.24). This bag waspacked together with the pH indicating device according to ProductionExample 6 and a mixed gas of 10% CO₂-90% air in a bag (secondarypackaging member) made of nylon (15 μm thick)-polyvinyl alcohol (18 μmthick)-polyethylene (60 μm thick) laminated film (space volume 400 ml)to provide a medical solution package according to the invention.

Medical Solution Formulas (Compartment I) A solution containing thefollowing components in each 300 ml Calcium chloride dihydrate 0.2 gMagnesium sulfate heptahydrate 0.3 g Glucose (USP) 0.8 g (CompartmentII) A solution containing the following components in each 700 ml Sodiumchloride 7.3 g Potassium chloride 0.3 g Sodium bicarbonate 1.9 gPotassium phosphate, dibasic heptahydrate (USP) 0.2 g

Using an injection needle (27G, Terumo, Neolus), a pinhole (about 500 μmin major diameter and about 50 μm in minor diameter) was pierced throughthe secondary packaging member of the above medical solution package ofthe invention and the change in color was monitored.

After 18 hours, the indicating device was purple and at this point oftime the carbon dioxide gas fraction within the secondary package was0.41% and the pH of a mixture of the solutions for the two compartmentswas 7.36.

What is claimed is:
 1. A bicarbonate-containing medicinal solutionpackage comprising a gas-permeable plastic container holding abicarbonate-containing medical solution and a gas-impermeable plasticpackaging member containing said gas-permeable plastic container, with acarbon dioxide atmosphere established in a space between said containerand packaging member and said space further containing a pH indicatingdevice comprising a gas-permeable plastic packet containing abicarbonate-containing fluid and a pH-indicator undergoing a change incolor in response to a change in pH of said fluid.
 2. Thebicarbonate-containing medical solution package according to claim 1wherein said pH-indicator is selected from the group consisting ofcresol red, m-cresol purple, and phenol red.
 3. Thebicarbonate-containing medical solution package according to claim 1wherein the bicarbonate of the bicarbonate-containing medical solutionand/or the bicarbonate-containing fluid is sodium bicarbonate.
 4. Thebicarbonate-containing medical solution package according to claim 1wherein the carbon dioxide atmosphere is established by filling thespace between said container and packaging member with a carbondioxide-generating oxygen absorber or filling said space with a mixedgas containing carbon dioxide gas.
 5. The bicarbonate-containing medicalsolution package according to claim 1 wherein the bicarbonate-containingmedical solution is a medical solution selected from the groupconsisting of an antidote, an artificial kidney dialysate, a peritonealdialysate, an infusion, a dental root canal enlarging agent, anartificial cerebrospinal fluid, an intraocular irrigating solution, acardiac perfusate, a cardioplegic solution, a peritoneal irrigatingsolution and a solution for organ preservation.
 6. Thebicarbonate-containing medical solution package according to claim 1wherein said gas-permeable plastic container holding thebicarbonate-containing medical solution is a container comprising atleast two interconnected compartments isolated from one another by adivider and the bicarbonate-containing medical solution is contained inat least one of said compartments.
 7. The bicarbonate-containing medicalsolution package according to claim 1 wherein the gas-permeable plasticpacket of said pH indicating device comprises a laminated filmcomprising a polypropylene outer layer and a polyethylene inner layer.8. The bicarbonate-containing medical solution package according toclaim 7 wherein the polypropylene outer layer ispoly-4-methyl-1-pentene.
 9. A pH indicating device comprising agas-permeable plastic packet containing a bicarbonate-containing fluid,wherein said fluid is the medical solution in any of claims 1 through 8,and a pH-indicator having the property of undergoing a change in colorin response to a change in pH of said fluid.
 10. Thebicarbonate-containing medical solution package according to claim 2wherein the bicarbonate concentration of the bicarbonate-containingfluid is 0.05 to 2.0 w/v % and the pH-indicator is at a concentration of10 to 2000 ppm.